Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis thereby preventing cellular expansion under such conditions. The goal of this proposal is to determine the role of the endoplasmic reticulum stress response/Unfolded Protein Response (UPR) in sensing limitations in glucose availability and thereby facilitating cellular adaptation. PERK, one of three proximal signal transducers of the UPR plays a central role in mediating cell fate decisions. The pro-survival function of PERK has garnered it considerable interest from the point of view of developing small molecule inhibitors of its catalytic activity and the hope that such inhibitors would have potent anti-tumor activity. Indeed, in the previous funding cycle, we demonstrated that PERK inhibition is of potential clinical benefit in metastatic breast cancer. However, because PERK also pro-apoptotic and anti-proliferative activities, it could also exhibit tumor suppressive activity. Central our ability to effectively target PERK is a complete understanding of both its anti-proliferative/pro-apoptotic as well as pro-survival functions. In our preliminary work, we provide evidence that while PERK functions to facilitate melanoma progression, it paradoxically functions as a potent suppressor of melanoma initiation. In this proposal, we describe three integrated aims that focus on the elucidation of PERK function in melanoma initiation (Aim 1), the potential efficacy of anti-PERK targeted therapy (Aim 2) and the identification of tumor-derived PERK mutants and their role in tumor initiation/progression (Aim 3). These studies will provide critical new insight into the mechanisms whereby the PERK protein kinase regulates cell homeostasis in response to stress. The aims interface with Projects 1 and 2 through common interests in signaling pathways that sense and respond to metabolic limitation and through response and regulation of lipid metabolism. The findings steming from work proposed herein will provide a foundation for the design of novel anti-cancer therpeutics.